During amelogenesis a strong correlation has been repeatedly demonstrated between the amount of fluoride consumed and the incidence of dental fluorosis. Greater than optimal amounts of fluoride (taken systemically) have been shown to contribute to a greater risk in developing fluorosis in a dose dependent manner. Concurrent with the decline in dental caries has been an increase in the prevalence of dental fluorosis, a side effect of fluoride exposure. The prevalence of dental fluorosis in recent years ranges between 7.7% and 80.9% of the population in communities with fluoridated water and from 2.9% to 42% in communities with nonfluoridated water. We hypothesize that genetic determinants also influence to an individual's susceptibility or resistance to develop dental fluorosis. In other words, the environment interacts with the genotype to produce the final phenotype. Our initial test of this hypothesis consisted of using a mouse model system where continuous eruption of the mouse incisors permit investigation of active amelogenesis over a relatively short period of time and where we could rigorously control genotype, age, gender, food, housing, and drinking water fluoride level. That study involved 12 genealogically disparate inbred strains of mice, and showed differences in dental fluorosis susceptibility/resistance between the strains. Furthermore, we found clustering of strains into distinct phenotypic groups. The A/J mouse strain is highly susceptible, with a rapid onset and severe development of dental fluorosis compared to the other strains tested. The 129P3/J mouse strain is least affected with negligible dental fluorosis. Those observations directly support the contribution of a genetic component in the pathogenesis of dental fluorosis and have allowed us to develop a central hypothesis; that in addition to the environmental component (increased amounts of fluoride that can be ingested) genetic determinants/factors that encode proteins and pathways underlie fluorosis susceptibility or resistance. The goal of the proposed studies, to identify genes involved in dental fluorosis susceptibility/resistance, will be pursued in the following two specific aims. Specific Aim: To identify candidate loci that convey susceptibility / resistance to dental fluorosis. Two approaches will be used. First, through the modeling of gene action in the susceptible A/J strain and second, to perform quantitative trait loci (QTL) mapping using the A/J and 129P3/J inbred mouse strains in the generation of F2 progeny, and developing linkage maps at a resolution of 20-cM for the chromosomal regions containing putative susceptibility to fluorosis loci. These studies will allow us to identify genetic determinants that directly or indirectly contribute to an individual's susceptibility or resistance to dental fluorosis. Future studies will investigate the cellular roles and functions of these genes and pathways during the pathogenesis of fluorosis. This knowledge will allow optimal use of fluorides for an individual in the prevention of dental caries while minimizing the risks of excessive fluoride. [unreadable] [unreadable]